Electronic (e-)cigarettes are by far the fastest growing segment of the non-combustible tobacco market available to smokers. Most studies of e-cigarettes are 1) lab-based studies of either pharmacokinetics or toxicant exposure 2) cross-sectional studies of prevalence and predictors of use or, more rarely, 3) uncontrolled cohort studies. The three randomized studies to date, all based outside the US, are cessation- focused and thus do not say anything about the natural process by which smokers adopt e-cigarettes, and how such adoption changes smoking behavior. Studies of naturalistic, self-determined used are important to understand real-world impact of e-cigarettes. Many of the existing studies are limited by methodological issues that constrain interpretation: selection bias resulting from comparisons of self-selected users vs. non-users, retrospective or cross-sectional designs that inhibit causal inferences, absence of biomarkers of exposure, and/or insufficient sample size. The absence of prospective, randomized but still ecological studies is a glaring omission in the literature. In fact, there has yet to be a study that a) randomizes smokers to e-cigarettes vs. not, b) is focused on naturalistic outcomes that occur in real time, c) is prospective, with sufficient follow-up duration, d) provides data on nicotine/tobacco exposure, e) is of sufficient sample size, and f) is US-based, an important consideration given upcoming regulatory changes. We know of no published study with even two of these criteria. We propose a nationwide randomized clinical trial in which smokers (N=660) are randomized to receive samples of e-cigarettes vs. not. Randomization will be 2:1 to increase precision of uptake outcomes (Aim 1). A subset of smokers (n=120) will be recruited locally, to assess the impact of e-cigarette use on biomarkers of exposure (Aim 2). Finally, though ours is not a cessation study, it would be a missed opportunity if we did not track cessation outcomes (Aim 3) or sufficiently power the trial to detect differences if they emerge. Thus, our study is designed and powered to address a comprehensive set of outcomes along three themes: 1) uptake and patterns of use, 2) biomarkers of exposure, and 3) changes in smoking. Importantly, these, dynamic changes will be captured in real time as they naturally unfold. We believe this will be the best test to date of the naturalistic population impact of e-cigarettes. Methods are strengthened by 1) large sample size (the largest e-cigarette RCT), 2) nationwide recruitment, with 3) locally recruited subset to assess biomarkers, and 4) multiple measures of outcome. The strong investigative team, coupled with our success in prior studies using similar methodology, collectively enhances the probability of success in achieving grant aims. We believe this study will offer an important contribution to the e-cigarette literature, and offer considerable implications for tobacco control, including vital information for regulatory agencies such as the FDA.